Stroke. 1995;26:1409-1414
(Stroke. 1995;26:1409-1414.)
© 1995 American Heart Association, Inc.
Cigarette Smoking Accelerates Carotid Artery Intimal Hyperplasia in a Dose-Dependent Manner
Presented at the 20th International Joint Conference on Stroke and
Cerebral Circulation, Charleston, SC, February 9-11, 1995.
Pavel V. Petrik, MD;
Hugh A. Gelabert, MD;
Wesley S. Moore, MD;
William Quinones-Baldrich, MD
Michael M. Law, MD
From the Section of Vascular Surgery, University of California at Los
Angeles School of Medicine.
Correspondence to Hugh A. Gelabert, MD, UCLA School of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90024.
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Abstract
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Background and Purpose Intimal hyperplasia is the single most
important
cause of early restenosis after carotid
endarterectomy. Cigarette
smoking is an independent
risk factor associated with peripheral
vascular disease and
cerebrovascular accidents. We undertook
a dose-response experiment to
determine the effect of cigarette
smoke on development of intimal
hyperplasia in a rat carotid
artery intimal injury model.
Methods Seventy-two rats were divided into six equal groups and
underwent standardized balloon injury to the carotid artery. Each group
received 0 (controls), 1, 2, 3, 6, or 8 cigarettes per day for 4 weeks.
Resultant intimal hyperplasia was expressed as a percentage of original
lumen replaced by intimal hyperplasia.
Results Percent intimal hyperplasia development (±SD) was as
follows: controls (0 cigarettes per day), 17.7±13.2; 1 cigarette per
day, 22.8±15.0; 2 cigarettes per day, 20.0±14.7; 3 cigarettes per
day, 19.2±12.1; 6 cigarettes per day, 43.5±15.5; and 8 cigarettes per
day, 36.7±9.8. Six and 8 cigarettes per day significantly increased
the development of intimal hyperplasia after intimal injury
(P<.01).
Conclusions High-dose cigarette smoke accelerates development of
intimal hyperplasia and may pose a significant risk factor in
developing carotid restenosis.
Key Words: carotid arteries cigarette smoking hyperplasia rats
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Introduction
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Stroke is the third leading cause of
death in the United States
and is associated with a high rate of
morbidity.
1 There are
approximately 500 000 new stroke
victims in the United States
each year, and in 200 000 of these cases
death quickly follows.
At any one time, approximately one million
stroke victims are
alive and disabled.
2 Carotid
endarterectomy provides a means
of restoring blood
flow to affected cerebral areas and reduces
the incidence of subsequent
stroke.
3 4 As the number of carotid
endarterectomies
performed in this country increases, so does
the diversity of opinion
regarding all elements of the operation.
Proponents of carotid
endarterectomy have sought to identify
means of
reducing both early and late surgical morbidity to
improve surgical
outcome.
Among the surgical complications targeted by these efforts is the
problem of recurrent carotid stenosis. Restenosis rates
of greater than 50% diameter reduction vary from 4% to
22%.5 6 7 8 9 10 11 12 13 Because of this, noninvasive monitoring of the
carotid artery at regular intervals postoperatively, with surgery for
stenosis greater than 80%, has been
recommended.10 The majority of recurrent stenoses
remain asymptomatic, and in most series symptoms are
limited to severe lesions. The lack of data on the natural history of
severe stenosis and on the risk factors for stenosis development preclude an informed
decision on the role of surveillance or surgery.
Numerous risk factors have been investigated for an association with
restenosis, including age,10 14 15
sex,6 11 13 15 16 17 diabetes,6 10 and
smoking,6 15 16 17 18 each with varying results. Smoking in
particular has demonstrated mixed results. We investigated the
dose-response effect of cigarette smoke on the development of intimal
hyperplasia in a well-described animal model.
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Materials and Methods
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Seventy-two (six groups of 12 each) Sprague-Dawley
rats weighing
300 to 500 g were placed in a smoking
apparatus (detailed below)
and exposed to increasing
amounts of cigarette smoke daily until
doses of 1, 2, 3, 6, and 8
cigarettes per day were achieved.
Animals received their target smoke
dosing for 1 week and then
underwent standardized balloon injury of the
carotid artery
intima.
Our technique for standardized arterial balloon injury
involves unilateral dissection of the right common carotid artery and
cannulation of the external carotid artery. A 2F Fogarty balloon
catheter (American Edwards Labs) was inserted and passed proximally
toward the aortic arch. The balloon was inflated to 2 atm (Namic Co,
Angiographic System Division) and withdrawn to the carotid artery
bifurcation, resulting in denudation of the
endothelium. The procedure was repeated three times
with 120° rotation of the catheter between passes. This technique has
been shown to induce a reproducible injury and has been used
extensively in our laboratory.
The animals were exposed to cigarette smoke in an apparatus
designed at the University of Kentucky for small animal smoke
dosing.19 20 Rats were placed into individual wire
containers that restrained them such that only their snouts were
exposed in the intake port of the container. Eight rats restrained in
this manner were then placed onto the exhaust manifold of the smoke
machine at a time (Fig 1
). Puffing was simulated by
placing a lighted standard reference research cigarette (R1F4
cigarettes, University of Kentucky Tobacco and Health Research
Institute) into a holder and subjecting it to 1 second of vacuum at
1-minute intervals. Smoke was conducted to the exhaust port by means of
Tygon tubing (Norton Performance Plastics). Excess smoke was
evacuated from the exhaust manifold by a separate vacuum source. The
system was tuned such that 10 "puffs" fully consumed one
cigarette. Rats were allowed 10-minute rest periods between each
cigarette. The animals were exposed to their target dose of cigarette
smoke 5 days a week for 4 weeks.

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Figure 1. Diagram shows apparatus used for small
animal smoke dosing. Note eight rats restrained in wire containers with
snouts placed into individual exhaust ports. A lighted cigarette is
present within the timed vacuum container.
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The vessels were then harvested by injection of 10 mL of 1%
glutaraldehyde into the aortic root at systemic
pressure to provide in vivo fixation while anatomic dimensions were
maintained. After several minutes the animals were killed, and the
arterial specimens were placed in 10% buffered
formaldehyde. Three serial cross sections through the midportion of
each artery were stained with Verhoeffvan Gieson stain by a
professional histology laboratory (VCA Clinical Lab, Los Angeles,
Calif).
The slide-mounted arterial lesions were studied with the
use of morphometric analysis to quantitate the size of the
intimal hyperplastic lesion. Photomicrographs of the stained sections
were taken at a power of x80. Using a digital desktop planimeter
(Lasico Graphic Digitizers) that converts tracings made by a hand-held
cursor into units of length and area, we calculated the absolute
cross-sectional area occupied by the intimal hyperplasia lesion and the
circumference of the internal elastic lamina (IEL). Using this
measurement of the IEL, we calculated the radius of the vessel by the
following mathematical formula: Circumference (IEL measurement)=2
r;
r=IEL/2
. Substituting this value of r into the formula
r2 allows for calculation of a normalized luminal area.
The hyperplastic lesion was then expressed as a percentage of the
luminal area, allowing comparison among vessels of differing
caliber.
Animal care complied with the "Principles of Laboratory Animal
Care" (formulated by the National Society for Medical Research) and
the Guide for the Care and Use of Laboratory Animals
(National Institutes of Health publication No. 86-23, revised
1985).
Statistical analysis of intimal hyperplasia percent differences
between controls and smoke-exposure groups included ANOVA and
Dunnett's comparison.
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Results
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Four deaths occurred at the time of preinjury smoke exposure,
and
six animals died after initial arterial injury. These
animals
were replaced with similarly pretreated animals. During the
4-week
course of postinjury smoking, the following deaths per group
occurred:
4 controls, 1 one-cigarette-per-day animal, 3
two-cigarettes-per-day
animals, 1 six-cigarettes-per-day animal, and 5
eight-cigarettes-per-day
animals. Control animals and several smoking
cohort deaths were
secondary to carotid artery stripping as evidenced
by listless
behavior, poor appetite, and partial paralysis immediately
after
recovery from anesthesia. These animals failed to
recover over
a period of time and were killed. At the time of vessel
harvesting,
no wound infections or other surgical complications were
noted.
The results of the planimetric intimal hyperplasia/IEL calculations are
summarized in the Table
. An index of 0.00% indicates no
intimal hyperplasia; 100% would represent complete occlusion.
No statistical differences were shown in intimal hyperplasia percentage
ratios between controls and animals exposed to low-dose (1, 2, and 3
cigarettes per day) cigarette smoke (P>.05). Animals
receiving high doses of cigarette smoke (6 or 8 cigarettes per day) had
statistically increased intimal hyperplasia percentage ratios compared
with controls (P<.01).
Fig 2
shows a control artery with a large amount of
intimal hyperplasia 4 weeks after a balloon catheter injury. Fig 3
shows an arterial cross section 4 weeks
after a similar balloon catheter endothelial denudation
and low-dose (1, 2, or 3 cigarettes per day) smoke exposure. The most
significant amounts of intimal hyperplasia were demonstrated in animals
exposed to high-dose (6 or more cigarettes per day) smoke for 4 weeks
after balloon catheter injury (Fig 4
).

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Figure 2. Photomicrograph of control (untreated) rat carotid
artery after balloon catheter injury. Note internal elastic lamina
(IEL) demarcating vessel lumen with enclosed intimal hyperplasia (IH)
lesion (Verhoeffvan Gieson stain; original magnification x80).
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Figure 3. Photomicrograph of artery exposed to low-dose (2 to
3 cigarettes per day) smoke for 4 weeks shows moderate increase in
degree of intimal hyperplasia (IH) (Verhoeffvan Gieson stain;
original magnification x80). IEL indicates internal elastic
lamina.
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Figure 4. Photomicrograph shows marked increase in development
of intimal hyperplasia (IH) after exposure to high-dose (3 to 6
cigarettes per day) smoke for 4 weeks (Verhoeffvan Gieson stain;
original magnification x80). IEL indicates internal elastic
lamina.
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Discussion
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Recurrent arterial stenosis, first
reported in the carotid artery
by Stoney and String in
1976,
21 had been recognized years earlier
as contributing
to vascular reconstructive failures.
22 23 Numerous
studies
suggest that the majority of stenoses are fibroproliferative
lesions
of intimal hyperplasia that develop within 2 years of surgery
and
are asymptomatic when
discovered.
6 11 12 13 16 17 24 25 26 27 Studies following up
patients after carotid endarterectomy
with serial
duplex ultrasound of the carotid artery demonstrate
variable rates
of restenosis; a greater than 50% diameter reduction
was
demonstrated in 4% to 22% of patients,
5 6 7 8 9 10 11 12 13 and Park et
al
7 demonstrated 50% to 75% stenosis in 8.5%
of
patients and greater than 80% stenosis in 4% of patients
followed
up for a mean of 47 months after carotid
endarterectomy. Although
controversy exists as to
the indications for reoperation, most
clinicians currently recommend
reoperation for symptomatic patients
or those with greater
than 80% stenosis.
10
As a result of the frequency of restenosis after carotid
endarterectomy and the morbidity associated with
reoperation, many investigators have searched for risk factors
associated with restenosis. Numerous patient-dependent
characteristics have been investigated for association with an
increased incidence of restenosis, including
age,10 14 15 sex,6 11 13 15 16 17
diabetes,6 10 and smoking,6 15 16 17 18 each with
varying results. Smoking, in particular, has demonstrated mixed
results. Clagett et al15 and Reilly et al18
showed an increased incidence of restenosis in smokers, whereas
Atnip et al,6 Ouriel and Green,17 and
Thomas et al16 found no such relationship. We have
demonstrated that exposure to high-dose cigarette smoke increases
development of intimal hyperplasia in the injured carotid artery.
Previous clinical studies on the relationship between smoking and
restenosis rates after carotid
endarterectomy have been hampered by problems with
sample size and accuracy of data on smoking habits. In addition, since
most studies involve analysis of multiple factors, attempts at
univariate analysis may not represent the
true effect of cigarette smoke alone. Our study used equal numbers in
each cohort group and in controls to ensure uniformity of effect among
all groups studied. We also analyzed the dose-response effect
of cigarette smoke on the development of intimal hyperplasia using a
standard animal model to allow for study of a single variable in a
controlled environment. Although control animals were not restrained in
a manner similar to that of smoke-exposed animals during the course of
the experiment, previous work in our laboratory demonstrated no
significant differences in intimal hyperplasia development between
restrained and unrestrained control animals (M.M.L, unpublished data,
1994).
The animals used in this study develop lesions after
endothelial denudation similar to those found in areas
of human intimal hyperplasia. This model has been used extensively by
our laboratory and other investigators28 29 30 31 32 33 34 35 36 37 in studies of
intimal hyperplasia. Although there are differences between the rat
balloon catheter injury model compared with human restenosis
after carotid endarterectomy, both processes
involve the development of intimal hyperplasia. This process is usually
attenuated in rats after 6 weeks but continues unabated in human
lesions. Our model harvests the carotid artery 4 weeks after intimal
injury to obtain hyperplastic lesions during the active proliferation
phase (similar to that found in humans after intimal injury). Damage to
the endothelium and media is a prominent feature in
this model, as it is in human arteries after carotid
endarterectomy, balloon angioplasty,
atherectomy, and vein grafting. These lesions consist of a thickened
intima with abundant smooth muscle cells and matrix (collagen, elastin,
and proteoglycans); human lesions display prolific matrix but
relatively fewer smooth muscle cells.23 38 39 40 41 42 43 44 45 46
Endothelial denudation is followed by platelet
adherence to the exposed thrombogenic subendothelium.
Platelets then spread and release vasoactive and thrombogenic
factors, as well as growth factors (platelet-derived growth factor,
transforming growth factor-ß, and epidermal growth
factor).47 These factors are mitogenic for
smooth muscle ingrowth and matrix deposition, with resultant intimal
hyperplasia formation.
We have demonstrated a statistically significant increase in the
development of intimal hyperplasia in the common carotid artery after
exposure to smoke from 6 or 8 cigarettes per day. Animals exposed to 3
or fewer cigarettes per day failed to demonstrate a significant
increase in intimal hyperplasia development. This suggests a threshold
level at which the stimulatory effect of cigarette smoke is expressed.
This effect of high-dose cigarette smoke may be secondary to
alterations in platelet, endothelial cell,
neutrophil, or smooth muscle cell functions or a combination thereof.
Many studies have demonstrated an increase in the number of
platelets or their activity after exposure to cigarette
smoke.48 49 50 51 52 Rangemark et al51 showed an
increase in both platelet number and in platelet/vessel wall
interaction with smoke exposure. These effects were not seen with
exposure to nicotine alone,49 and no sex differences were
noted.51 In addition to an increased ability to aggregate,
smoke also affects platelet biochemistry. Smith et
al53 54 demonstrated inhibition of platelet
mitochondrial activity after exposure to cigarette smoke. Although
smokers demonstrate chronic activation of their
platelets,50 the effect is
reversible.50 52
Endothelial cells are also affected by exposure to
cigarette smoke and may be responsible for the threshold effect seen
with high-dose exposure. Injury to the endothelium from
smoking disrupts normal regulatory properties and results in abnormal
endothelial cell function.55
Endothelial cell wall permeability is increased, as is
the likelihood of detachment with injury.56 In addition,
smokers demonstrate decreased endothelial cell DNA
synthesis.57 Similar to the reversible effects of
cigarette smoke on platelets, endothelial
dysfunction in smokers also does not appear to be
permanent.58 Although our model uses denudation of
endothelium to stimulate development of intimal
hyperplasia, exposure to cigarette smoke before injury may potentiate
the posttraumatic reaction of platelet and neutrophil stimulation
and smooth muscle cell recruitment. In some models of
atherosclerosis, for instance,
endothelial cell dysfunction in smokers was shown
before anatomic evidence of plaque formation was
seen.59
Neutrophils are responsible for the release of vasoactive and
mitogenic factors after injury and are integral to the
development of intimal hyperplasia after endothelial
injury. Smokers demonstrate alterations in neutrophil function at both
the cellular and molecular levels.49 56 60 61 62 63 64 65 Cigarette
smoke increases white blood cell counts49 and increases
the activation of neutrophils by the complement system.65
Chemotactic functions of neutrophils are affected by smoke
exposure,62 as is the production,60
composition,56 61 63 64 and release60 of
neutrophil granules. Because of the importance of neutrophils in the
initial stages of intimal hyperplasia development, any alterations in
function secondary to cigarette smoke would likely affect vessel
restenosis after injury.
Smooth muscle cell proliferation with associated extracellular matrix
deposition results in the development of the intimal hyperplasia
lesions actually responsible for luminal obstruction. Although the
increased smooth muscle cell proliferation found in smokers may be
secondary to endothelial and neutrophil dysfunction,
there is also evidence that cigarette smoke itself may be
responsible.55 66 67 68 Higman et al66
demonstrated smooth muscle cell proliferation, increased vasomotor
tone, and impaired endothelium-derived relaxation from
endothelium-derived relaxing factor in cigarette
smokers. He67 found increased smooth muscle cell
proliferation and migration to the intima of arteries after smoke
exposure with a concomitant increase in extracellular matrix
production. Polycyclic aromatic hydrocarbons in cigarette
smoke, often implicated in the development of atherogenesis, have also
been shown to increase smooth muscle cell proliferation and
viability.68
The primary purpose of our study was to demonstrate the clinical effect
of cigarette smoke on intimal hyperplasia. We did not seek to actually
isolate the particular component(s) responsible for this effect. We
hypothesize that exposure to carbon monoxide may play a role in the
augmentation of intimal hyperplasia development after
endothelial injury. Preliminary studies in this
laboratory (P.V.P. et al, unpublished data, 1994) have demonstrated
dose-responsive elevations in carbon monoxide and hemoglobin in rats
exposed to cigarette smoke in an identical apparatus.
Further immunohistochemical analysis with the use of monoclonal
antibodies is currently under way to isolate the component(s) of
intimal hyperplasia affected by cigarette smoke.
We conclude that high-dose cigarette smoke accelerates development of
intimal hyperplasia in the injured rat carotid artery. Because of the
similar intimal hyperplasia response in human carotid arteries after
endothelial damage, smoking likely represents a
significant risk factor in developing carotid restenosis and
stroke. This effect was not demonstrated with low-dose exposure to
cigarette smoke.
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Acknowledgments
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This study was supported in part by a grant from the Joash
Foundation
and the Veterans Administration merit review No. 911-040. We
would
like to thank Ted Henderson for performing the planimetry
measurements
and for his assistance with the care and preparation of
animal
subjects.
Received December 20, 1994;
revision received March 17, 1995;
accepted April 26, 1995.
 |
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